Prior to 2005, a major focus of T cell immunology dogma was directed to what is called a “TH1/TH2 paradigm”, which refers to the generally accepted roles of two T helper (TH) cell subsets. TH cells are lymphocytes that typically express the surface protein, CD4, and influence the establishment and capabilities of the immune system. Disease outcome has been routinely associated with a skewing toward one or the other of these T cell subsets. The rationale was based on the observation that the way in which antigen is introduced to antigen presenting cells (APCs), such as dendritic cells (DCs), determined which TH subset was preferentially activated, thus influencing how the immune system responded. For example, in the endogenous pathway triggered by direct infection of the DC with, e.g., a virus, the activated DCs produced interleukin-12 (IL-12) and this led to the specific stimulation of TH1 T cells. TH1 activation led to the production of interleukin-2 (IL-2) needed to drive IL-2-dependent CD8+ T cell immunity, which in turn led to direct lysis of infected cells. On the other hand, when antigen was presented to the DC via the exogenous pathway, such as by phagocytosis, the DC produced interleukin-10 (IL-10) leading to TH2 activation, the subsequent secretion of interleukin-4 (IL-4), and help for B cell production of antibody. Most disease pathology came to be associated with either cellular or humoral skewing of the immune response by the endogenous or exogenous presentation of antigen to the immune system. Where antibody was involved, TH2 were implicated, and when direct cytolytic activity was observed, for example in cell-mediated destruction of islets in Type I diabetes, it was assumed to be due to TH1 activity.
An additional player in the TH1/TH2 paradigm was the regulatory T cell (Treg). Treg function, which is generally directed to the modulation and deactivation of the immune response, was found to be dependent in the periphery (but not the thymus) on TGFβ and high IL-2 receptor expression. Treg, like TH2, produce IL-4, and Treg function in control of TH1 cells was thought to involve competition between TH1 and Treg for IL-2.
The exclusive trinity of TH1, TH2 and Treg changed in 2005 when investigators demonstrated, while knocking out the IL-12 gene, that immunity to fungal infections diminished. Careful study of the molecular rationale used to generate the IL-12 knockout mouse demonstrated that IL-12 shared a p40 common chain with another cytokine, interleukin-23 (IL-23). When the non-p40 chain unique to IL-23 was knocked out, TH1 function remained while fungal immunity continued to be thwarted (Cua et al, 2003; Murphy et al, 2003). It was soon discovered that the dominant cytokine responsible for fungal immunity was interleukin-17 (IL-17) and this was produced by what became known as TH17 T cells (Harrington et al, 2005) that are driven by DC-induced IL-23. IL-17 is not a growth factor for TH17 cells (Harrington et al, 2005; Langrish et al, 2005; Park et al, 2005), but instead recruits neutrophils and promotes granulopoiesis that leads to pathogen clearance.
TGFβ and interleukin-6 (IL-6) are two cytokines associated with TH17 development (Betteli et al, 2006; Mangen et al, 2006; Veldhoen et al, 2006). Under certain circumstances, TGFβ can be a growth factor for TH17 (Veldhoen et al, 2006), most prominently in the absence of Th1 or Th2 (Das et al, 2009), while in their presence may also function to suppress Th1 and Th2 development (Li et al, 2007). TGFβ is also a growth factor for regulatory T cells (Treg) (Korn et al, 2009). Competition between TH17 and Treg (Bettelli et al, 2006), to the detriment of the latter, is considered to be a mechanism whereby TH17 have been implicated in the induction of autoimmune disorders such as multiple sclerosis (Matusevicius et al, 1999; Lock et al, 2002), rheumatoid arthritis (Murphy et al, 2003; Kirkmam et al, 2006), type I diabetes (Vukkadapu et al, 2005; Bradshaw et al, 2009), psoriasis (Wilson et al, 2007; Krueger et al, 2007), uveitis (Luger et al, 2008), inflammatory bowel disease (Fujino et al, 2003; Duerr et al, 2006) and Crohn's disease (Schmidt et al, 2005; Fuss et al, 2006). The TH17-associated cytokine, IL-6, directly suppresses Treg differentiation as well (DeLuca et al, 2007; Korn et al, 2008). Accordingly, targeting TH17 or their inductive factors has been described as a potential means to treat autoimmune diseases (DeBenedetti, 2009; Pernis, 2009).
The molecular signatures of TH1, TH2, TH17 and Treg are controlled by the subset-specific transcription factors, T-bet, GATA-3, ROR (retinoic acid orphan receptor) and FoxP3, respectively. FoxP3 inhibits IL-2 transcription, thus giving Treg an avaricious appetite for exogenous sources of IL-2. ROR expression has been reported to be anti-proliferative.
TH17 T cells are induced in response to certain bacterial or fungal extracellular pathogens including Klebsiella pneumoniae, Bordatella pertussis, Streptococcus pneumoniae and Candida albicans (Ye, et al, 2001; Huang et al., J. Infect. Dis. 190:624-631 (2004), Happel et al, 2005; Higgens et al, 2006; DeLuca et al, 2007; Lu et al, 2008; Zhang et al, 2009). In general, these pathogens primarily colonize exposed surfaces such as airways, skin and the intestinal lumen (Peck and Mellins, 2009). This immune response has been reported to be elicited by interactions of microbial components with various pattern recognition receptors (PRRs) on the surface of APCs, including dectin-1 and Toll-like receptors (TLRs), which lead to activation of TH17 cells and other proinflammatory events (see, e.g., LeibundGut-Landmann et al., Nat. Immunol. 8(6)630-638 (2007); Acosta-Rodriguez, Nat. Immunol. 8(6):639-646 (2007); Taylor et al., Nat Immunol. 8(1): 31-38 (2007)). Activation of dectin-1 and various TLR pathways has been shown to result in reciprocal regulation of IL-23 and IL-12 pathways (see, e.g., Gerosa et al., J. Exp. Med. 205(6)1447-1461 (2008) and Dennehy et al., Eur J Immunol. 39(5):1379-1386 (2009)). TH17 clear microbial infections via the cytokine-mediated recruitment of neutrophils. There is also evidence for a role for TH17 against certain intracellular pathogens such as Listeria monocytogenes, Salmonella enteriditis, Toxoplasma gondii, Clamydia trachomatis and Mycobacterium tuberculosis (Harty and Bevan, 1995; Dalrymple et al, 1995; Cooper et al, 2002; Kelly et al, 2005; Khader et al, 2005; Schulz et al, 2008; Zhang et al, 2008) among others.
In the 1990's, yeast-based immunotherapy compositions were introduced as novel compositions for inducing immune responses through both the MHC class I-restricted and the MHC class II-restricted pathways of antigen-presenting cells (see U.S. Pat. No. 5,830,463). Although these compositions are initially exposed to the immune system as an exogenous antigen(s), yeast-based immunotherapy compositions are uniquely able to trigger the induction of both a CD8+ cytotoxic T cell response through cross-presentation of antigens by the MHC class I-restricted pathway, as well as a CD4+ T cell response through presentation of antigens by the MHC class II-restricted pathway (See, e.g., U.S. Pat. Nos. 5,830,463 and 7,083,787, Stubbs et al., Nat. Med. 7:625-629 (2001) and Lu et al., Cancer Research 64:5084-5088 (2004)). Yeast-based immunotherapy compositions stimulate pattern recognition receptors (PRR); upregulate adhesion molecules, costimulatory molecules, and MHC class I and class II molecules on antigen presenting cells including DCs; and induce the production of proinflammatory cytokines by antigen presenting cells (e.g., TNF-α and IL-12) (see, e.g., Stubbs et al., supra; Brown et al., J Exp. Med. 197:1119-1124 (2003)).
In the context of yeast-based immunotherapeutic compositions, which may be engineered to express one or more antigens, the complexities of the mechanism of action of yeast-based immunotherapeutics with respect to the immune system and therapeutic efficacy have not yet been fully identified. It is desirable to better understand how different individuals respond to immunization with yeast-based immunotherapy compositions, and thereby be able to manipulate and personalize immunotherapeutic strategies to more effectively elicit a desired immune response that is most appropriate for a given disease or condition in an individual.